Propylphosphonic anhydride → 2-Cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2h-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate

HRID 472009Notes

Reaction equation

HRID 472009 reaction equation
[C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH:52]([C:54](O)=[O:55])[CH2:51][NH:50][C:49]=2[CH:57]=1>CC1CCCO1.C(OCC)(=O)C>[C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:54]([CH:52]2[O:53][C:48]3[CH:47]=[CH:46][C:45]([O:44][C:43]([F:59])([F:42])[F:58])=[CH:57][C:49]=3[NH:50][CH2:51]2)=[O:55])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1

Participants

6

Reactant 3

HCID 111923Propylphosphonic anhydrideHCID 59394952HCID 59394952, compoundHCID 593949626-(trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

Product 1

HCID 593950202-Cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2h-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

5-Amino-2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)phenyl methyl carbonate (150 mg, 0.47 mmol) was dissolved in 2-methyltetrahydrofuran (3 mL) and T3P (754 mg, 705 μL of 50% w/w, 1.18 mmol). 6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (125 mg, 0.47 mmol) was added portion-wise over 30 min. After 3 h the reaction was diluted with ethyl acetate, washed with 10% saturated NaHCO3 (2×20 mL) and brine. The solution was dried over Na2SO4, filtered, and dried down to an orange solid. Purification by silica gel chromatography (1% methanol/dichloromethane) provided 2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate as a colorless oil. LC/MS m/z 562.2 [M+H]+. The oil was dissolved in methanol (3 mL) and treated with NaOH (0.5 mL of 5 M, 2.4 mmol) and stirred for 5 min. Water (5 mL) and saturated NaHCO3 (2 mL) were added until a white precipitate formed. The product was extracted into ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide N-(4-cyclopentyl-2-(3-(dimethylamino)prop-1-ynyl)-5-hydroxyphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide as a off-white solid (90 mg, 34% yield). LC/MS m/z 504.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.16 (s, 1H), 9.25 (s, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.52-6.49 (m, 1H), 4.91 (dd, J=3.0, 6.3 Hz, 1H), 4.32 (t, J=3.8 Hz, 2H), 3.54 (dd, J=3.0, 12.2 Hz, 1H), 3.42 (dd, J=6.3, 12.3 Hz, 1H), 3.14 (quin, J=8.4 Hz, 1H), 2.85 (d, J=4.4 Hz, 6H), 1.91 (m, 2H), 1.72 (m, 2H), 1.63-1.60 (m, 2H), 1.48 (m, 2H).

Workup

  1. washwashed with 10% saturated NaHCO3 (2×20 mL) and brine
  2. dry with materialThe solution was dried over Na2SO4
  3. filtrationfiltered
  4. customdried down to an orange solid
  5. customPurification by silica gel chromatography (1% methanol/dichloromethane)

Sources & evidence

ORD record
ord-d548d666cca94090ac54ddcb18007915
Source dataset
uspto-grants-2014_01
Patent number
US08633189B2

Reaction notes

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